The primary goal of this Program Project is to use a synergistic combination of genomics, molecular genetics and natural products chemistry to identify and purify potentially useful secondary metabolites of the filamentous fungus Aspergillus nidulans. The recently published sequencing of genomes of three species of Aspergillus has revealed that these species have a surprisingly large number of secondary metabolism pathways that are potential sources of new and useful natural products. The products of most of the A. nidulans secondary metabolism pathways are currently unknown and the three research groups will work together towards the goal of identifying and purifying the product(s) of each of the secondary metabolism gene clusters in A. nidulans. Project #1 is headed by Dr. Berl Oakley at Ohio State University, the overall P.I., who will develop tools for systematic promoter exchanges and for the systematic disruption of genes through targeted gene replacements. A complete library of A. nidulans strains carrying deletions of key nonribosomal peptide synthetase or polyketide synthase genes will be created. Project #2 is headed by Dr. Nancy Keller at the University of Wisconsin, who will focus on chromatin mutants to enhance the production of minimally expressed clusters and to activate "silent" clusters. Project #3 is headed by Dr. Clay Wang at the University of Southern California, who will focus on isolation and characterization of secondary metabolites produced by A. nidulans strains from the Oakley and Keller laboratories. In summary, this multidisciplinary collaboration will discover new secondary metabolites from Aspergillus nidulans and develop methods that can be used to mine the secondary metabolomes of other species of fungi for valuable natural products. Relevance to public health: The three investigators will use a multi-disciplinary synergistic approach directed towards elucidating the products of previously unexplored secondary metabolite biosynthesis pathways of the organism Aspergillus nidulans. We expect the project to generate a large number of exciting new natural products for testing and development as a new generation of chemotherapeutics, antimicrobials and other medically valuable classes of compounds.